Associations have been reported of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both attentiondeficit͞hyperactivity disorder and the personality trait of novelty seeking. This polymorphism occurs in a 48-bp tandem repeat in the coding region of DRD4, with the most common allele containing four repeats (4R) and rarer variants containing 2-11. Here we show by DNA resequencing͞haplotyping of 600 DRD4 alleles, representing a worldwide population sample, that the origin of 2R-6R alleles can be explained by simple one-step recombination͞mutation events. In contrast, the 7R allele is not simply related to the other common alleles, differing by greater than six recombinations͞mutations. Strong linkage disequilibrium was found between the 7R allele and surrounding DRD4 polymorphisms, suggesting that this allele is at least 5-10-fold ''younger'' than the common 4R allele. Based on an observed bias toward nonsynonymous amino acid changes, the unusual DNA sequence organization, and the strong linkage disequilibrium surrounding the DRD4 7R allele, we propose that this allele originated as a rare mutational event that nevertheless increased to high frequency in human populations by positive selection.

Associations of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder have been reported. Recently, on the basis of the unusual DNA sequence organization of the DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare mutational event that increased to high frequency by positive selection. We now have resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from individuals of African, European, Asian, North and South American, and Pacific Island ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the region examined, with more polymorphisms observed in DNA samples from African individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we estimate that the 7R allele arose prior to the upper Paleolithic era (approximately 40000-50000 years ago). Further, the pattern of recombination at these polymorphic sites is the pattern expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose a model for selection at the DRD4 locus consistent with these observed LD patterns and with the known biochemical and physiological differences between receptor variants.

Highly conserved repetitive DNA sequence clones, largely consisting of (GGAAT HeLa-ceil nuclear proteins recognize this sequence with a relative affinity >105. The extreme evolutionary conservation ofthis DNA sequence, its centromeric location, its unusual hydrogen bonding properties, its high affinity for specific nuclear proteins, and its similarity to functional centromeres isolated from yeast suggest that this sequence may be a component of the functional human centromere.

Activation of the mammalian heat shock transcription factor (HSF)1 by stress is a multistep process resulting in the transcription of heat shock genes. Coincident with these events is the rapid and reversible redistribution of HSF1 to discrete nuclear structures termed HSF1 granules, whose function is still unknown. Key features are that the number of granules correlates with cell ploidy, suggesting the existence of a chromosomal target. Here we show that in humans, HSF1 granules localize to the 9q11-q12 heterochromatic region. Within this locus, HSF1 binds through direct DNA–protein interaction with a nucleosome-containing subclass of satellite III repeats. HSF1 granule formation only requires the DNA binding competence and the trimerization of the factor. This is the first example of a transcriptional activator that accumulates transiently and reversibly on a chromosome-specific heterochromatic locus.

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Telomeres are the ends of linear eukaryotic chromosomes. To ensure that no large stretches of uncharacterized DNA remain between the ends of the human working draft sequence and the ends of each chromosome, we would need to connect the sequences of the telomeres to the working draft sequence. But telomeres have an unusual DNA sequence composition and organization that makes them particularly difficult to isolate and analyse. Here we use specialized linear yeast artificial chromosome clones, each carrying a large telomere-terminal fragment of human DNA, to integrate most human telomeres with the working draft sequence. Subtelomeric sequence structure appears to vary widely, mainly as a result of large differences in subtelomeric repeat sequence abundance and organization at individual telomeres. Many subtelomeric regions appear to be gene-rich, matching both known and unknown expressed genes. This indicates that human subtelomeric regions are not simply buffers of nonfunctional 'junk DNA' next to the molecular telomere, but are instead functional parts of the expressed genome.

There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated.

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30 year-old population-based health survey (N=310, age range 90–109; the 90+ Study) were genotyped/resequenced at the DRD4 gene, and compared to a European ancestry-matched younger population (N=2902, age range 7–45). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p=3.5 × 10−9), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knockout mice, when compared to wild-type and heterozygous mice, displayed a 7–9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.